Introduction
Endoscopic retrograde cholangiopancreatography (ERCP) plays an important role in the
inspection and treatment of biliary neoplasms. However, ERCP is an invasive treatment,
and the frequency of post-ERCP pancreatitis (PEP) was reported to be 10–15 % in patients
with naïve papilla [1]
[2]
[3]
[4]. Several studies have shown that the demographic and clinical risk factors for PEP
include younger age (< 60 years), female sex, sphincter of Oddi dysfunction, a history
of recurrent pancreatitis, and a history of PEP. Procedure-related risk factors for
PEP include endoscopic papillary balloon dilation, pancreatic sphincterotomy, precut
sphincterotomy, pancreatic duct injection, and repeated cannulation attempts [3]
[5]
[6]
[7]. However, few studies have described the risk factors for PEP in specific biliary
diseases, which may be important because ERCP-related procedures vary depending on
the disease. This variability in ERCP-related procedures is particularly pronounced
in the treatment of biliary neoplasms. Multiple ERCP-related procedures, such as endoscopic
biliary drainage (EBD), intraductal ultrasound (IDUS), and transpapillary biliary
duct biopsy, are often also performed when treating biliary neoplasm. It is important
to further clarify the method in terms of preventing PEP in patients with biliary
neoplasm because these patients may undergo surgery to remove the neoplasm after ERCP
and such surgery will be complicated if PEP develops.
Several studies report preventative methods for PEP, including the administration
of nonsteroidal anti-inflammatory drugs (NSAIDs) before ERCP, pancreatic duct stenting,
and wire-guided cannulation [8]
[9]
[10]
[11]
[12]
[13]. In addition, some endoscopists perform endoscopic sphincterotomy (ES) before biliary
duct stent placement, IDUS, or transpapillary biliary duct biopsy because ES reduces
tension at the pancreatic duct orifice and is therefore thought to help prevent PEP
[14]. A recent meta-analysis also demonstrated that ES was associated with a lower risk
of PEP in patients undergoing biliary stenting for bile leak [12].
This retrospective, multicenter study aimed to clarify the effectiveness of ES in
the prevention of PEP in patients treated for biliary neoplasms. In cases of ES performed
in patients with biliary neoplasm, the use of techniques such as biliary duct stent
placement, IDUS, and/or transpapillary biliary duct biopsy may introduce bias regarding
technical risk factors for PEP. We therefore undertook a propensity score analysis,
which can balance the effects of many confounding risk factors.
Materials and methods
This retrospective, multicenter cohort study was approved by the institutional review
boards of the three participating university hospitals.
Patients
The cohort consisted of all consecutive patients with biliary tract tumors who underwent
ERCP for the first time between January 2006 and December 2016 at three tertiary care
medical centers in Japan (Wakayama Medical University, Kindai University, and Osaka
Medical University). Patients were excluded from the study if they were < 20 years
old, had a history of acute pancreatitis, and/or had previously undergone gastrectomy,
EBD, and/or ES.
ERCP procedures and post-procedural care
All patients provided informed consent before ERCP. All procedures were conducted
by endoscopists who had performed > 200 ERCPs in total before this study. ERCP was
performed according to a standard technique under intravenous sedation. In cases where
cannulation was difficult, precut sphincterotomy or the double-wire technique was
performed. After successful selective cannulation, cholangiography was performed to
verify the biliary neoplasm. In addition, all patients received protease inhibitors.
ERCP-related procedures (biliary duct stent placement, IDUS, and/or transpapillary
biliary duct biopsy) were conducted to inspect the biliary neoplasm and treat the
biliary obstruction. ES was performed using an electrosurgical generator in 120 Watt
ENDO CUT mode with a papillotomy knife (CleverCut, Olympus Medical Systems) in all
patients. The incision range was small (incision reached the hooding fold) or medium
(incision reached up to a portion of the hooding fold) in all patients. Biliary duct
stent placement was performed using a plastic stent (PS), a metal stent (MS), or an
endoscopic naso-biliary drainage tube. The type of biliary stent was decided by the
endoscopist, but a MS was only used in patients with inoperable cancer. MSs were uncovered
or fully covered with a diameter of 10 mm. Covered MSs were only placed across the
papilla with ES. IDUS was conducted using a 3D-IDUS probe (UM-DG20-31 R, Olympus Medical
Systems). Transpapillary biliary duct biopsy was conducted using biopsy forceps (Radial
Jaw 3GP/4P, Boston Scientific, or FB-38 W or FB19N-1, Olympus Medical Systems). Biliary
biopsy with forceps was performed under X-ray fluoroscopy using the following four
techniques according to previous reports [15]
[16]: direct insertion of forceps with the free-hand technique without ES, wire-guided
insertion of forceps with a side slit for the guidewire without ES, wire-guided insertion
of forceps with grasping the guidewire without ES, and direct insertion of forceps
with the free-hand technique with ES. Pancreatic duct stents were placed at the discretion
of the endoscopist [15]
[16]. Transpapillary biliary duct biopsy was performed 3–4 times.
On the first day after treatment, all patients underwent a physical examination and
blood testing. When PEP occurred, the patients were treated immediately. Complications
arising post-ERCP were recorded as early (in the first week) or late (more than 1
week after ERCP).
Data collection
The following baseline demographic and clinical data were obtained from the medical
records: age, sex, body mass index, type and location of biliary neoplasm, and presence
of common bile duct dilatation ( ≥ 8 mm), peripapillary diverticulum, obstructive
jaundice, and cholangitis. The bile duct diameter was defined as the common bile duct
diameter on computed tomography, endoscopic ultrasound, or magnetic resonance cholangiopancreatography.
When the neoplasm was in the common bile duct, measurement on the liver side was taken
as the bile duct diameter.
The following procedural characteristics were also obtained from the medical records:
total procedural time (from endoscope insertion to endoscope removal), cannulation
method (whether wire-guided cannulation was used), and whether ES, biliary duct stent
placement, IDUS, transpapillary biliary duct biopsy, pancreatic duct injection, double-wire
technique, precut sphincterotomy, and pancreatic duct stent placement were performed.
In addition, the use of NSAIDs was recorded and whether cholecystectomy was performed
and if the tumor was treated operatively. Cannulation success was recorded along with
the clinical symptoms and serum amylase levels 18–24 hours after the procedure.
Outcomes
The outcome was the frequency of PEP. PEP was considered to be present when the patient
experienced abdominal pain for ≥24 hours after ERCP and had high serum amylase levels
(three times the upper limit of normal) 18–24 hours after the procedure [17]. Another end point was effectiveness of ES for preventing PEP in subgroups. Biliary
stent placement (PS placement, MS placement and MS placement across the papilla),
IDUS, and transpapillary biliary duct biopsy are the final purposes of ERCP, particularly
for biliary neoplasm and were therefore selected for subgroup analysis to evaluate
the effectiveness of ES for preventing PEP. However, other technical risk factors,
such as pancreatic duct injection, wire-guided cannulation, double guidewire technique,
and precut, were performed to accomplish these purposes. Therefore, pancreatic duct
injection, wire-guided cannulation, double guidewire technique, and precut were not
selected as subgroups for analysis. The frequency of PEP in each group (ES and non-ES)
was compared between patients with PSs and MSs. Other end points were the frequency
of severe PEP, duration of the fasting period required to treat PEP, and the frequency
of non-PEP complications after ERCP (perforation, biliary infection, bleeding, and
any complications that required hospital treatment). PEP severity was classified according
to Cotton’s criteria [17]: mild (requiring 2–3 days of hospital treatment), moderate (4–10 days of hospital
treatment), or severe (> 10 days of hospital treatment, requiring surgical or intensive
treatment, or where PEP contributed to the death of the patient) [14].
Statistical analysis
Demographic, pre-ERCP clinical, and ERCP procedural factors were compared between
the ES and non-ES groups using the Chi-squared test. Propensity score matching analysis
was performed. The propensity score calculated for each patient was based on logistic
regression analysis of factors considered to affect PEP. These factors were selected
using a forward stepwise method because many factors affect PEP. Using these propensity
scores, cases and controls were matched one-to-one [18]
[19]
[20]. Specifically, one-to-one matching was performed for the ES and non-ES groups ([Fig. 1]) using nearest neighbor matching with a caliper coefficient of 0.2. After matching,
the incidence of PEP was compared between the matched ES and non-ES groups.
Fig. 1 Schematic representation of propensity score matching analysis. In an effort to balance
the patient group, propensity score analysis was used to generate a set of matched
cases and controls. The propensity score was calculated for 362 patients based on
a logistic analysis of clinical characteristics indicated by stepwise regression analysis
(e. g. wire-guided cannulation, placement of biliary stent, NSAID administration,
and transpapillary biliary duct biopsy). Using propensity scores, 86 patients were
selected from 95 patients undergoing ES, and 86 patients from 267 patients in the
non-ES group. ES, endoscopic sphincterotomy; NSAID, nonsteroidal anti-inflammatory
drug.
In the five subgroups of patients who underwent biliary duct stent placement, PS placement,
MS placement, IDUS, and transpapillary biliary duct biopsy, pre-ERCP clinical and
ERCP procedural data were compared in patients with and without PEP by Chi-squared
test. These univariate analyses were performed on data from the subgroups. Log binomial
regression analysis was then used to identify factors related to PEP in the subgroups.
In these subgroup analyses, propensity score matching was inappropriate because the
number of matched pairs was small. Factors were included in each regression analysis
if the P value of the univariate test for that variable was < 0.10; this P value was selected because of the exploratory nature of the study. Precut sphincterotomy
and NSAID use were not included in the subgroup regression analyses because the numbers
of patients who underwent these treatments were too small. ES was included in all
regression analyses irrespective of statistical significance on univariate analysis
in order to assess its ability to predict PEP. In the subgroups of patients who underwent
biliary duct MS placement across the papilla, pre-ERCP clinical and ERCP procedural
data were compared between patients with and without PEP using Fisher’s exact test.
The frequency of PEP in each group (ES and non-ES) was compared between patients with
PSs and MSs using the Chi-squared test.
All statistical analyses were performed using JMP (Version Pro 13.0) and R (version
3.4.1) software. For all analyses, P values of < 0.05 were considered to indicate statistical significance.
Results
In total, 362 patients with a mean age of 71.0 years were enrolled in the study. Of
these, 12.9 % were < 60 years old and 46.2 % were female; 16.8 % and 4.4 % had a body
mass index > 25 kg/m2 and a history of cholecystectomy, respectively. In addition, 50.4 %, 14.0 %, 17.9 %,
2.2 %, and 5.5 % had extrahepatic cholangiocarcinoma, papillary carcinoma, hilar cholangiocarcinoma,
intrahepatic cholangiocarcinoma, and gallbladder carcinoma, respectively ([Table 1]). At the time of ERCP, 63.9 %, 57.3 %, 12.9 %, and 8.8 % had common bile duct dilatation,
jaundice, cholangitis, and periampullary diverticulum, respectively. The mean total
ERCP procedural time was 29.9 minutes; additional procedures were wire-guided cannulation
(65.5 %), ES (26.2 %), biliary duct stent placement (84.0 %), IDUS (31.8 %), transpapillary
biliary duct biopsy (23.6 %), pancreatic duct injection (45.6 %), double guidewire
technique (14.6 %), precut sphincterotomy (3.6 %), and pancreatic duct stent placement
(5.0 %). In addition, 4.7 % received NSAIDs and 32.2 % underwent operative treatment
on the biliary duct tumor.
Table 1
Demographic, pre-ERCP clinical, and ERCP procedural characteristics of the whole cohort
of patients with biliary neoplasms (n = 362).
|
Variables
|
n (%)
|
|
Younger age, < 60 years
|
47 (12.9)
|
|
Female sex
|
168 (46.2)
|
|
Body mass index > 25 kg/m2
|
61 (16.8)
|
|
Biliary tumor type
|
|
|
187 (50.4)
|
|
|
51 (14.0)
|
|
|
65 (17.9)
|
|
|
8 (2.2)
|
|
|
20 (5.5)
|
|
|
31 (8.5)
|
|
Common bile duct dilatation, ≥ 8 mm
|
232 (63.9)
|
|
Periampullary diverticulum
|
32 (8.8)
|
|
Jaundice at ERCP
|
208 (57.3)
|
|
Pancreatic duct obstruction
|
3 (0.8)
|
|
History of cholecystectomy
|
16 (4.4)
|
|
Cholangitis
|
47 (12.9)
|
|
Operative treatment on biliary duct tumor
|
117 (32.2)
|
|
Cannulation success
|
352 (97.2)
|
|
Median total procedural time, minutes
|
29.9
|
|
Underwent wire-guided cannulation
|
237 (65.5)
|
|
ES
|
95 (26.2)
|
|
|
14 (3.9)
|
|
|
81 (22.3)
|
|
Biliary duct stent placement
|
304 (84.0)
|
|
Biliary duct stent type
|
|
|
68 (19.5)
|
|
|
93 (25.6)
|
|
|
143 (38.6)
|
|
Stent placement across the papilla
|
260 (71.8)
|
|
IDUS
|
115 (31.8)
|
|
Transpapillary biliary duct biopsy
|
85 (23.6)
|
|
Pancreatic duct injection
|
165 (45.6)
|
|
Double guidewire technique
|
53 (14.6)
|
|
Precut sphincterotomy
|
13 (3.6)
|
|
Pancreatic duct stent placement
|
18 (5.0)
|
|
Administered NSAIDs
|
17 (4.7)
|
ERCP, endoscopic retrograde cholangiopancreatography; ES, endoscopic sphincterotomy;
ENBD, endoscopic naso-biliary drainage; IDUS, intraductal ultrasound; NSAIDs, nonsteroidal
anti-inflammatory drugs.
Complications associated with ERCP
PEP occurred in 84 patients (23.2 %). It was mild, moderate, and severe in 61 (16.8 %),
16 (4.4 %), and 7 patients (1.9 %), respectively ([Table 2]). The mean fasting period required to treat PEP was 4.97 days. Soon after ERCP,
three (0.8 %) and two (0.5 %) patients developed bleeding and biliary infection, respectively.
Three (0.8 %) developed cholangitis as a late post-ERCP complication.
Table 2
Complications associated with ERCP in patients with biliary neoplasm (n = 362).
|
Variables
|
n (%)
|
|
Overall
|
92 (25.4)
|
|
Early complications[1]
|
|
|
84 (23.2)
|
|
|
61 (16.8)
|
|
|
16 (4.4)
|
|
|
7 (1.9)
|
|
|
3 (0.8)
|
|
|
2 (0.5)
|
|
Late complications[3]
|
|
|
3 (0.8)
|
ERCP, endoscopic retrograde cholangiopancreatography.
1 Complications in the first 7 days after ERCP.
2 PEP severity was classified according to Cotton’s criteria [14].
3 Complications arising > 7 days after ERCP.
Patient characteristics in the ES versus non-ES group
The characteristics of the ES and non-ES groups are shown in [Table 3]. Differences were seen between the groups in the number of patients experiencing
a long procedural time and the number undergoing wire-guided cannulation, IDUS, transpapillary
biliary duct biopsy, pancreatic duct injection, double guidewire technique, precut
sphincterotomy, and biliary duct stent placement. NSAID administration differed between
the two groups.
Table 3
Patient characteristics.
|
Variables
|
All patients
|
Patients selected by propensity matching
|
|
ES group
n = 95
|
Non-ES group
n = 267
|
P value[1]
|
ES group after matching
n = 86
|
Non-ES group after matching
n = 86
|
P value[1]
|
|
Younger age, < 60 years
|
9 (9.5)
|
38 (14.2)
|
0.23
|
7 (8.1)
|
13 (15.2)
|
0.15
|
|
Female sex
|
44 (46.4)
|
124 (46.4)
|
0.98
|
38 (44.2)
|
34 (39.5)
|
0.53
|
|
Body mass index > 25 kg/m2
|
18 (19.0)
|
43 (16.2)
|
0.53
|
17 (19.8)
|
17 (19.8)
|
1.00
|
|
Biliary tumor location
|
|
|
8 (8.4)
|
44 (16.5)
|
0.05
|
7 (8.1)
|
15 (17.4)
|
0.07
|
|
|
17 (18.0)
|
56 (21.0)
|
0.52
|
15 (17.4)
|
13 (15.1)
|
0.68
|
|
|
70 (73.7)
|
167 (62.7)
|
0.05
|
64 (74.4)
|
58 (67.4)
|
0.31
|
|
Common bile duct diameter < 8 mm
|
34 (35.8)
|
96 (36.0)
|
0.98
|
29 (33.7)
|
25 (29.1)
|
0.51
|
|
Periampullary diverticulum
|
3 (3.2)
|
29 (10.9)
|
0.02
|
3 (3.5)
|
4 (4.7)
|
0.70
|
|
Jaundice at ERCP
|
61 (64.2)
|
147 (55.1)
|
0.12
|
56 (65.1)
|
52 (60.5)
|
0.53
|
|
Long procedural time, > 40 min
|
48 (50.5)
|
89 (33.3)
|
0.003[1]
|
43 (50.0)
|
32 (37.2)
|
0.09
|
|
Wire-guided cannulation
|
84 (88.4)
|
157 (57.3)
|
< 0.001[1]
|
75 (87.2)
|
75 (87.2)
|
1.00
|
|
IDUS
|
42 (41.2)
|
73 (27.3)
|
0.002[1]
|
38 (44.2)
|
30 (34.9)
|
0.21
|
|
Transpapillary biliary duct biopsy
|
34 (35.8)
|
51 (19.2)
|
0.001[1]
|
30 (34.9)
|
30 (34.9)
|
1.00
|
|
Pancreatic duct injection
|
52 (54.7)
|
113 (42.3)
|
0.04[1]
|
46 (53.5)
|
47 (54.7)
|
0.87
|
|
Double guidewire technique
|
21 (22.1)
|
32 (12.0)
|
0.02[1]
|
17 (19.8)
|
17 (19.8)
|
1.00
|
|
Precut sphincterotomy
|
7 (7.4)
|
6 (2.3)
|
0.02[1]
|
5 (5.8)
|
2 (2.5)
|
0.25
|
|
Pancreatic duct stent placement
|
5 (5.3)
|
13 (4.9)
|
0.88
|
4 (4.7)
|
5 (5.8)
|
0.73
|
|
Biliary duct stent placement
|
87 (91.6)
|
217 (81.3)
|
0.02[1]
|
78 (90.7)
|
78 (90.7)
|
1.00
|
|
NSAID administration
|
11 (11.6)
|
6 (2.3)
|
0.0002[1]
|
4 (4.7)
|
4 (4.7)
|
1.00
|
ERCP, endoscopic retrograde cholangiopancreatography; non-ES, endoscopic sphincterotomy
not performed; ES, endoscopic sphincterotomy; IDUS, intraductal ultrasound; NSAIDs,
nonsteroidal anti-inflammatory drugs.
The data are shown as n (%). P values were calculated using the Chi-squared test.
1
P values < 0.05 (bold) were considered to be significant.
PEP in the ES versus non-ES group
To minimize the effect of selection bias between the two groups, we performed propensity
score matching analysis based on risk factors (cannulation method type, transpapillary
biliary duct biopsy, biliary duct stent placement, and NSAIDs), which were chosen
by a stepwise method, and selected 86 matched cases in each group in a one-to-one
manner.
The C-statistic calculated from the receiver operating characteristic curve of our
model was 0.74, showing that our model had a good ability to distinguish ES patients
from non-ES patients. After matching, there was no evidence for differences between
in patient clinical characteristics or procedural characteristics in the two groups,
apart from the statistically significant difference in the risk factors for PEP ([Table 3]). The incidence of PEP in the matched ES group was lower than that in the non-ES
group (19.7 % vs. 33.7 %, P = 0.04; Odds Ratio (OR) = 0.47, 95 % Confidence interval (CI): 0.23–0.96). The incidence
of each severity of PEP and other complications did not differ between the two groups
([Table 4]).
Table 4
Complications associated with ERCP in ES and non-ES groups after propensity score
matching.
|
Variables
|
ES group after matching
n = 86
|
Non-ES group after matching
n = 86
|
P value
|
OR
|
95 %CI
|
|
PEP
|
17 (19.7)
|
29 (33.7)
|
0.04[1]
|
0.47
|
0.23–0.96
|
|
|
15 (17.4)
|
23 (26.7)
|
0.14
|
0.57
|
0.28–1.20
|
|
|
1 (1.1)
|
2 (2.3)
|
0.56
|
0.49
|
0.06–3.86
|
|
|
1 (1.1)
|
4 (4.7)
|
0.17
|
0.24
|
0.04–1.65
|
|
Bleeding
|
3 (3.4)
|
0 (0)
|
0.24
|
Inf
|
Inf
|
|
Cholangitis
|
1 (1.0)
|
0 (0)
|
1.00
|
Inf
|
Inf
|
OR, odds ratio; CI, Confidence interval; PEP, post-ERCP pancreatitis; non-ES, endoscopic
sphincterotomy not performed; ES, endoscopic sphincterotomy; Inf, infinity.
The data are shown as n (%). P values were calculated using the Chi-squared test.
1
P values < 0.05 (bold) were considered to be significant.
Frequency of PEP according to the stent type (PSs versus MSs)
There were no evidence for differences in the frequency of PEP between patients with
PSs and MSs in the ES group (16.7 % vs. 30.3 %, P = 0.14, OR = 0.46, 95 %CI: 0.17–1.26) and the non-ES group (21.4 % vs. 34.3 %, P = 0.10, OR = 0.52, 95 %CI: 0.24–1.13) ([Table 5]).
Table 5
Frequency of PEP in patients with plastic and metal stents.
|
Variable
|
ES group
n = 87
|
Non-ES group
n = 217
|
|
Plastic stent
n = 54
|
Metal stent
n = 33
|
P value
|
OR
|
95 %CI
|
Plastic stent
n = 182
|
Metal stent
n = 35
|
P value
|
OR
|
95 %CI
|
|
PEP
|
9 (16.7 %)
|
10 (30.3 %)
|
0.14
|
0.46
|
0.17–1.26
|
39 (21.4 %)
|
12 (34.3 %)
|
0.10
|
0.52
|
0.24–1.13
|
OR, odds ratio; CI, Confidence interval; PEP, post-ERCP pancreatitis; non-ES, endoscopic
sphincterotomy not performed; ES, endoscopic sphincterotomy.
Frequency of PEP according to the incision range of ES (small versus medium)
There was no evidence for differences in the frequency of PEP between patients with
small and medium incision ranges (28.6 % vs. 21.0 %; P = 0.53, OR = 0.64, 95 %CI 0.19–2.38).
Risk factors for PEP in patients undergoing biliary duct stent placement, PS placement,
MS placement, IDUS, and transpapillary biliary duct biopsy
Univariable and multivariable analyses in the 304 patients who underwent biliary duct
stent placement showed that jaundice at ERCP (RR = 1.60; P = 0.03), pancreatic duct injection (RR = 2.01; P = 0.002), and double guidewire cannulation (RR = 1.54; P = 0.04) were considered to be independent risk factors for PEP ([Table 6]). Univariable and multivariable analyses of patients with PSs showed that non-ES
was a risk factor for PEP (RR = 1.95; P = 0.03) (Supplementary table 1). Univariable and multivariable analyses of patients with MSs showed that, statistically,
there was no evidence that non-ES was a risk factor for PEP. In addition, there was
no evidence that the number of patients without ES differed between the PEP and non-PEP
groups among patients with MS placement across the papilla (Supplementary tables 2 and 3). However, the number of patients without ES was higher in the PEP group than in
the non-PEP group among patients without biliary duct stent placement (P= 0.03) (Supplementary table 4).
Table 6
Risk factors for PEP in patients who underwent biliary duct stent placement.
|
Variables
|
Univariable analysis[1]
|
Multivariable analysis
|
|
PEP
n = 70
|
No PEP
n = 234
|
P value[1]
|
RR
|
P value
|
|
Younger age, < 60 years
|
10 (14.2)
|
31 (13.2)
|
0.82
|
|
|
|
Female sex
|
35 (50.0)
|
100 (42.7)
|
0.28
|
|
|
|
Body mass index > 25 kg/m2
|
11 (15.7)
|
33 (14.1)
|
0.70
|
|
|
|
Biliary location of tumor
|
|
|
9 (12.8)
|
35 (14.9)
|
0.67
|
|
|
|
|
17 (24.2)
|
42 (17.9)
|
0.56
|
|
|
|
|
44 (62.8)
|
157 (67.1)
|
0.63
|
|
|
|
Common bile duct diameter < 8 mm
|
26 (37.1)
|
75 (32.0)
|
0.42
|
|
|
|
Periampullary diverticulum
|
8 (11.4)
|
17 (7.3)
|
0.27
|
|
|
|
Jaundice at ERCP
|
51 (72.8)
|
134 (49.6)
|
0.03[1]
|
1.60
|
0.03[1]
|
|
Long procedural time, > 40 min
|
33 (47.1)
|
81 (34.6)
|
0.06
|
1.38
|
0.10
|
|
Cannulation method type[2]
|
19 (27.1)
|
84 (35.9)
|
0.17
|
|
|
|
Non-ES
|
49 (70.0)
|
168 (71.8)
|
0.77
|
1.05
|
0.81
|
|
IDUS
|
16 (22.9)
|
84 (35.9)
|
0.04[1]
|
0.51
|
0.01[1]
|
|
Placement metal stent
|
23 (32.9)
|
48 (20.5)
|
0.04[1]
|
0.91
|
0.64
|
|
Stent placement across the papilla
|
58 (82.8)
|
202 (86.3)
|
0.47
|
|
|
|
Transpapillary biliary duct biopsy
|
14 (20.0)
|
54 (23.1)
|
0.73
|
|
|
|
Pancreatic duct injection
|
43 (61.4)
|
92 (39.3)
|
0.001
|
2.01
|
0.002[1]
|
|
Double guidewire technique
|
21 (30.0)
|
25 (10.7)
|
0.001
|
1.54
|
0.04[1]
|
|
Pancreatic duct stent placement
|
1 (1.4)
|
14 (6.0)
|
0.21
|
|
|
ERCP, endoscopic retrograde cholangiopancreatography; non-ES, endoscopic sphincterotomy
not performed; IDUS, intraductal ultrasound; RR, Relative risk; PEP, post-ERCP pancreatitis.
The data are shown as n (%).
1 Univariable analyses were performed using Chi-squared tests. P values of < 0.05 (bold) were considered to be sufficiently significant for inclusion
in the logistic regression analysis.
2 Not guided by wire.
Univariable and multivariable analyses of the 115 patients who underwent IDUS showed
that non-ES (RR = 4.54; P = 0.01) and a long procedural time (RR = 2.89; P = 0.01; [Table 7]) were statistically significant risk factors for PEP.
Table 7
Risk factors for post-ERCP pancreatitis in patients who underwent intraductal ultrasound.
|
Variables
|
Univariable analysis[1]
|
Multivariable analysis
|
|
PEP
n = 21
|
No PEP
n = 94
|
P value[1]
|
OR
|
P value
|
|
Younger age, < 60 years
|
2 (9.5)
|
10 (10.6)
|
0.87
|
|
|
|
Female sex
|
10 (47.6)
|
41 (43.6)
|
0.74
|
|
|
|
Body mass index > 25 kg/m2
|
3 (14.2)
|
18 (19.1)
|
0.60
|
|
|
|
Biliary location of tumor
|
|
|
4 (19.0)
|
17 (18.1)
|
0.67
|
|
|
|
|
2 (9.5)
|
11 (11.7)
|
0.56
|
|
|
|
|
15 (71.4)
|
66 (70.2)
|
0.63
|
|
|
|
Common bile duct diameter < 8 mm
|
6 (28.5)
|
33 (35.1)
|
0.57
|
|
|
|
Periampullary diverticulum
|
2 (9.5)
|
5 (5.3)
|
0.47
|
|
|
|
Jaundice at ERCP
|
16 (76.1)
|
53 (56.4)
|
0.09
|
1.99
|
0.11
|
|
Long procedural time, > 40 min
|
15 (71.4)
|
42 (44.7)
|
0.03[1]
|
2.89
|
0.01[1]
|
|
Cannulation method type[2]
|
2 (9.5)
|
21 (22.3)
|
0.18
|
|
|
|
Non-ES
|
18 (85.7)
|
55 (58.5)
|
0.02
|
4.54
|
0.01[1]
|
|
Transpapillary biliary duct biopsy
|
9 (42.9)
|
43 (45.7)
|
0.81
|
|
|
|
Pancreatic duct injection
|
15 (71.4)
|
57 (60.6)
|
0.36
|
|
|
|
Double guidewire cannulation
|
3 (14.2)
|
9 (9.6)
|
0.52
|
|
|
|
Biliary duct stent placement
|
16 (76.1)
|
84 (87.5)
|
0.11
|
|
|
|
Pancreatic duct stent placement
|
1 (4.76)
|
1 (1.06)
|
0.33
|
|
|
ERCP, endoscopic retrograde cholangiopancreatography; non-ES, endoscopic sphincterotomy
not performed; IDUS, intraductal ultrasound; OR, odds ratio; PEP, post-ERCP pancreatitis.
The data are shown as n (%).
1 Univariable analyses were performed using Chi-squared tests. P values of < 0.05 (bold) were considered significant and included in the logistic
regression analysis.
2 Not guided by wire.
Univariable and multivariable analyses of the 85 patients who underwent transpapillary
biliary duct biopsy showed that female sex (RR = 5.25; P = 0.03) and non-ES (RR = 5.26; P = 0.017) were risk factors for PEP in this group of patients ([Table 8]).
Table 8
Risk factors for PEP in the patients who underwent transpapillary bile duct biopsy.
|
Variables
|
Univariable analysis[1]
|
Multivariable analysis
|
|
PEP
n = 18
|
No PEP
n = 67
|
P value
|
RR
|
P value
|
|
Younger age, < 60 years
|
2 (11.1)
|
9 (13.3)
|
0.79
|
|
|
|
Female
|
13 (72.2)
|
27 (40.3)
|
0.02[1]
|
5.25
|
0.03[1]
|
|
Body mass index > 25 kg/m2
|
5 (27.8)
|
17 (25.0)
|
0.84
|
|
|
|
Biliary location of tumor
|
|
|
3 (16.7)
|
4 (6.0)
|
0.16
|
|
|
|
|
13 (72.2)
|
51 (76.1)
|
0.76
|
|
|
|
|
2 (11.1)
|
12 (17.9)
|
0.72
|
|
|
|
Common bile duct diameter < 8 mm
|
10 (55.6)
|
20 (29.9)
|
0.04[1]
|
1.52
|
0.32
|
|
Periampullary diverticulum
|
2 (11.1)
|
4 (6.0)
|
0.45
|
|
|
|
Jaundice at ERCP
|
12 (66.7)
|
34 (50.8)
|
0.23
|
|
|
|
Long procedural time, > 40 min
|
11 (61.1)
|
33 (49.3)
|
0.37
|
|
|
|
Cannulation method type[2]
|
3 (16.7)
|
13 (19.4)
|
0.79
|
|
|
|
Non-ES
|
16 (88.9)
|
35 (52.2)
|
0.005[1]
|
5.26
|
0.017[1]
|
|
IDUS
|
9 (50.0)
|
43 (64.2)
|
0.27
|
|
|
|
Pancreatic duct injection
|
12 (66.7)
|
39 (58.2)
|
0.52
|
|
|
|
Double guidewire cannulation
|
5 (27.7)
|
6 (9.0)
|
0.03[1]
|
1.50
|
0.29
|
|
Biliary duct stent placement
|
14 (77.8)
|
51 (76.1)
|
0.88
|
|
|
|
Pancreatic duct stent placement
|
0 (0)
|
4 (5.97)
|
0.57
|
|
|
ERCP, endoscopic retrograde cholangiopancreatography; non-ES, endoscopic sphincterotomy
not performed; IDUS, intraductal ultrasound; RR, relative risk; PEP, post-ERCP pancreatitis.
The data are shown as n (%).
1 Univariable analyses were performed using Chi-squared tests. P values of < 0.05 (bold) were considered significant and included in the logistic
regression analysis.
2 Not guided by wire.
Discussion
In this study, 23.2 % of patients who underwent ERCP for biliary duct tumors developed
PEP; the rate of severe PEP was 1.9 %. This incidence of PEP and severe PEP is higher
than that reported in previous studies (5–15 % and 0.3–1.0 %, respectively) and may
reflect the fact that the current study focused on biliary duct tumors with naive
papilla, whereas previous studies examined PEP in patients with a variety of diseases
[1]
[2]
[3]
[4]. After performing propensity score matching to minimize the effect of selection
bias between the groups, the frequency of PEP was lower in the ES group than in the
non-ES group. This study suggests that ES is an effective method for preventing PEP
in patients with biliary duct neoplasm.
ES is a common and often essential procedure in therapeutic ERCP. In the present study,
PEP risk factors were more commonly seen in the ES group, which may influence the
outcome and mask the true effectiveness of ES. Therefore, propensity score matching
analysis was undertaken to minimize the effects of any inherent bias and to reduce
the effects of confounding factors identified in observational studies [18]
[20]
[21]. Recent studies reported that treatment effects from randomized trials and propensity
score analysis were similar in similar populations [22]. In this study, matching effectively eliminated differences in clinical characteristics
between the ES and non-ES groups, including the risk factors for PEP. After matching,
ES decreased the incidence of PEP. However, after propensity score matching, the incidence
of PEP in the non-ES group (33.7 %) was higher than previously reported [2]
[3]
[4]. This may be because the percentage of patients with a risk factor for PEP increased
after propensity score matching.
Some previous studies have reported that ES increases the frequency of PEP. For example,
a large case series conducted by Rabenstein et al. (2000) showed ES to be associated
with a high rate of PEP [23]. Akashi et al. (2002) reported that this association reflects the sensitivity of
the pancreatic duct to ES-induced thermal damage, which generates edema in the surrounding
tissues and temporarily blocks the pancreatic duct [24]. The retrospective cohort study by Kawakubo et al. (2012) reported that, in patients
with malignant biliary obstruction, those who did not undergo ES were not at increased
risk of PEP after transpapillary biliary stent placement [25]. However, several other studies demonstrated a protective effect associated with
ES in patients undergoing biliary stenting. First, the randomized controlled trial
by Zhou et al. (2012) showed that not conducting ES before intraductal placement of
self-expanding MSs increased the rate of PEP in patients with malignant obstructive
biliary disease [26]. Sofi et al. (2016) reported that ES before biliary stenting is protective against
PEP in patients with bile leak [12]. Therefore, whether ES is protective or actually increases the risk of PEP remains
controversial.
Our subgroup analyses showed that, in patients with placement of biliary duct stent,
injection of contrast agent into the pancreatic duct and double guidewire technique
were independent risk factors for PEP. Non-ES, however, was not an independent risk
factor for PEP in these patients. In addition, ES did not effectively prevent PEP
in patients with MSs or even in patients who underwent MS placement across the papilla.
In contrast, non-ES was seen to be an independent risk factor for PEP in patients
who underwent PS placement, IDUS, and transpapillary biopsy. In addition, ES did not
effectively prevent PEP in patients without biliary duct stent placement. This suggests
that ES is more effective in the prevention of PEP in patients undergoing PS placement,
IDUS and transpapillary biopsy than in patients undergoing MS placement. It is reported
that ES can lower the risk of PEP by reducing tension at the pancreatic duct orifice
[14]
[27]. It is also thought that ES is effective in the prevention of PEP when performing
multiple transpapillary procedures during ERCP. Alternatively, MS placement may obstruct
the pancreatic duct orifice so much that ES cannot decrease the tension. ES more effectively
prevented PEP in patients undergoing PS placement, and the incidence of PEP tended
to be higher in patients with MSs regardless of whether ES was performed.
ES is associated with life-threatening complications, such as bleeding and perforation
[21]. Assessment of adverse events in the present study showed that bleeding due to ES
was observed in 3 % of patients, although no cases were life-threatening. These observations
are consistent with those reported in an earlier study [23]. Several studies also reported that ES before biliary stenting increases the risk
of cholangitis in patients with proximal bile duct obstruction [26]
[28]. However, in this study, cholangitis was not increased in the ES group and adverse
events associated with ES rarely resulted in major clinical issues. ERCP is often
repeated to treat stent occlusion and for further examination of biliary neoplasms,
and ES is thought to protect against PEP not only following the first ERCP but also
following subsequent procedures.
The principal limitations of this study are that the data were collected retrospectively
and therefore may be subject to selection and information bias. Due to the small number
of patients, some of the differences between patients were not statistically significant.
This study reports exploratory analysis, which is another limitation. In this study,
only MSs with a diameter of 10 mm were used. All patients with covered MSs underwent
ES. Therefore, it was difficult to compare covered and uncovered MSs, as well as MSs
with different diameters, in this study.
In addition, because this study assessed the risk factors for PEP after ERCP for biliary
neoplasms, we did not exclude cases of exposed ampullary carcinoma, in which ES is
difficult. A randomized controlled trial is required to confirm our findings regarding
the effect of ES on PEP in patients with biliary neoplasms.
There are two considerations regarding limitations of the statistical analysis in
this study. First, propensity score matching, despite its popularity, is problematic
and sometimes increases, rather than reduces, bias. Second, variables are selected
in this log binomial model using P values. In this study, factors used in multivariable analysis were selected based
on the results of univariable analyses, meaning type I errors may have occurred. Therefore,
there are limitations regarding the adjustment of bias.
In conclusion, the frequency of PEP was lower in the ES group than in the non-ES group. ES
may therefore be a useful method for preventing PEP in patients with biliary neoplasm,
particularly when performing transpapillary biopsy and IDUS.
